One-pot eschenmoser episulfide contractions in DMSO: Applications to the synthesis of fuligocandins A and B and a number of vinylogous amides

Article abstract of DOI:10.1021/jo101864n

Practical total syntheses of the natural products fuligocandin A (2a) and fuligocandin B (3) have been achieved through a convergent strategy depending on the Eschenmoser episulfide contraction as a key step. Conducting the reaction in DMSO proved to be an efficient and general method for the synthesis of a variety of vinylogous amides, such as azepan-2- ylidenepropan-2-one. 2011 American Chemical Society.

Full text of DOI:10.1021/jo101864n

ARTICLE
pubs.acs.org/joc
One-Pot Eschenmoser Episulfide Contractions in DMSO:
Applications to the Synthesis of Fuligocandins A and B and
a Number of Vinylogous Amides
Birgitta Pettersson, Vedran Hasimbegovic, and Jan Bergman*
Unit of Organic Chemistry, Department of Biosciences at Novum, Karolinska Institute, SE-141 57 Huddinge, Sweden
S Supporting Information
b
ABSTRACT: Practical total syntheses of the natural products
fuligocandin A (2a) and fuligocandin B (3) have been achieved
through a convergent strategy depending on the Eschenmoser
episulfide contraction as a key step. Conducting the reaction in
DMSO proved to be an efficient and general method for the
synthesis of a variety of vinylogous amides, such as azepan-2-
ylidenepropan-2-one.
’ INTRODUCTION
to the synthesis of a number of natural products8 and has been the
subject of an excellent review by Shiosaki.9
In 2004, Nakatani et al. investigated an extract of the fruit
bodies of the myxomycete Fuligo candida and isolated cycloan-
thraniloproline 1 and its derivatives 2a, 3, and 4 (Figure 1),
whose structures where established largely by extensive NMR
and MS studies.1 Fuligocandin A (2a), obtained as colorless
plates, was found to be the major constituent of the EtOAc-
soluble fraction, while fuligocandin B (3) was isolated as a yellow
pigment. A recent study has shown that fuligocandin B (3)
sensitizes leukemia cells to apoptosis caused by a tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL).2 Prompted
by this interesting biological activity and our ongoing interest
in cycloanthranilylproline-derived natural products we aimed
at developing practical syntheses of both fuligocandin A
and B.3
In addition to having the tricyclic cycloanthraniloproline core
structure, both fuligocandin A and B contain a vinylogous amide
function (Figure 1). Vinylogous amides are versatile reactants; i.
e., they can act as ambient electrophiles but also as nucleophiles
and are, furthermore, able to participate in pericyclic and radical
processes, properties which endow them as valuable intermedi-
ates for synthesis of, e.g., natural products.4 One particularly
versatile and efficient method for preparation of vinylogous
amides depends on alkylation of thioamides with an appropriate
electrophilic reactant followed by extrusion of sulfur, resulting
in a new carbon-carbon bond. Although the episulfide contrac-
tion was first studied by Knott,5 it has emerged as an important
carbon-carbon bond-forming process ever since the Eschen-
moser-Woodward collaboration on vitamin B12, where it
constituted one of the key coupling reactions.6 This method,
presently known as the Eschenmoser episulfide contraction,7
has remained relatively unexplored although it has been applied
There are two versions of the Eschenmoser episulfide contrac-
tion,10 the first one depends on oxidative6,11 and the second one
on alkylative precoupling.7 The latter variant (Scheme 1) begins
by alkylation of thioamides (I) with enolizable R-halocarbonyl
compounds (II), followed by 4 π-electrocyclic closure of the
thiocarbonyl ylide (III) to the episulfide (IV), which upon
thiophile-promoted extrusion of sulfur gives rise to vinylogous
amides (V). This transformation is strongly dependent on the
structural features of both the electrophilic and the nucleo-
philic partner. Substrates that undergo the episulfide contraction
most readily are thioiminium salts obtainable from tertiary thioa-
mides. On the other hand, secondary thiomidates often require
harsher conditions, that is, stronger bases such as tert-butoxide,
higher temperatures and longer reaction times.12 The carbon-
carbon bond formation occurs under mild conditions when a
β-dicarbonyl halide is used (e.g., diethyl R-bromomalonate).12
A
problem that frequently encountered is reversibility of the
thioamide alkylation, which occurs when the electrophile bears a
nucleophilic leaving group, resulting in lower yields (<80%).13
However, retro-alkylation can be avoided by employing an electro-
phile bearing a non-nucleophilic leaving group, such as triflate.9
’ RESULTS AND DISCUSSION
As the pyrrolo-1,4-benzodiazepine derivative 1is readily prepared
from proline and isatoic anhydride,14 we considered it suitable as a
common intermediate for synthesis of both fuligocandin A and B via
Eschenmoser episulfide contraction. Success of this strategy
Received: September 21, 2010
Published: February 22, 2011
r
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will depend upon selective monothionation of cycloanthrali-
noproline 1 and for fuligocandin B also on a practical synthesis
of the intermediate R-haloketone 9.
(Scheme 3). Interestingly, attempted Wittig coupling between
6 and N-t-BOC derivative of indole-3-carbaldehye 7 failed
completely; instead, a rapid cleavage of the N-t-BOC group
was observed.
As outlined in Scheme 2, en route to 3 via 9, 1,3-dichloroa-
cetone 5 was selectively combined with triphenylphosphine, and
the resulting intermediate phosphonium salt was treated with a
base to give the desired monoylide 6.15 Attempts to couple the
aldehyde 7 with 6 failed even if the Wittig reaction was run in
refluxing methanol for 5 days. This failure can be explained by
delocalization of the nitrogen lone pair toward the carbonyl
group, rendering it nonelectrophilic toward the ylide 6. Hence,
an electron-withdrawing protecting group was attached to the
nitrogen atom in order to prevent the electron flow toward
the formyl group. Accordingly, the aldehyde 7 was protected
with benzenesulfonyl chloride to give 8a and alternatively with
p-nitrobenzenesulfonyl chloride (NsCl) to give 8b. Both alde-
hydes (8a and 8b) underwent a smooth Wittig reaction with the
phosphorus ylide 6, however, only when the reaction was conducted
in refluxing methanol. Other solvents such as benzene, DMSO,
H2O, and DMF gave no reaction or poor yields of the required
indole derivatives 9. Attempts to obtain compound 11 by bro-
minating the readily available molecule 3-(3-oxo-1-buteneyl)-
indole (10)16 with 2-pyrrolidone hydrotribromide failed since
the bromination had a strong preference for the pyrrole moiety
Next, the pyrrolo-1,4-benzodiazepine derivative 1 was readily
prepared by heating isatoic anhydride and L-proline in DMSO.14
Initial thionation attempts of 1 using literature methods pro-
ceeded in low yields due to poor selectivity. For example, when
thionation was conducted using Lawesson’s reagent in THF,
xylene, or benzene, we encountered problems with either recovery
of some unreacted diamide 1 or formation of the dithionated
byproduct in all cases. This selectivity problem was finally solved
by employing the P2S5-Py2 complex (prepared by heating P4S10
in pyridine)21 to obtain the known monothione 1217 in 85% yield
(Scheme 4).
With the monothione (12) in hand, we attempted to couple it
with chloroacetone in order to obtain fuligocandin A (2a) via
episulfide contraction. Initial attempts were based on previously
described standard reagents and conditions such as tert-butoxide
or triethylamine and triphenylphosphine in benzene or xylene at
high temperatures. However, NMR analysis of the crude product
mixtures indicated that the desired vinylogous amide was not
1
formed since the spectra obtained lacked the characteristic H
signal at 5.29 ppm and the 13C signal at 91.0 ppm. The failures to
obtain fuligocandin A under these conditions led us to try the
reaction in dimethyl sulfoxide as a solvent. We envisioned that
dimethyl sulfoxide would facilitate not only the initial SN2
alkylation but also the carbon-carbon bond formation by
exposing the carbanion toward the electrophilic sp2 carbon.
Indeed, preliminary experiments on the alkylated intermedi-
ate 13 using DBU as a base gave the desired alkaloid 2a in
acceptable yield (40%). However, fuligocandin A was ob-
tained in an excellent yield (98%) when DABCO was used
as a base and trimethyl phosphite as sulfur scavenger. The
unstable intermediate thioimidate 13 could be isolated, but
the best results were obtained when it was used immediately in
situ. The use of the relatively volatile trimethyl phosphite
instead of more commonly used triethyl phosphite simplified
the workup as it could be readily removed, along with its sulfur
analogue (trimethyl thiophosphonate) by coevaporation with
Figure 1. Alkaloids 1-4 isolated from Fuligo candida. Structures 2a and
3 represent fuligocandin A and B, respectively.
Scheme 1. General Mechanism for the Episulfide Contrac-
tion Reaction via Alkylative Precoupling (R = Alkyl, Phenyl)
Scheme 3. Attempted Synthesis of Compound 11
Scheme 2. Synthesis of the Indole Fragment of Fuligocandin B
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Scheme 4. Synthesis of Fuligocandins A and B
Figure 2. Nuclear Overhauser effect (NOE) correlations of 2a, 3, 20c, 22b.
ethanol. The resultant dark, semisolid residue was trituated
with ethanol to induce precipitation of fuligocandin A as an
off-white solid. Hence, a one-pot alkylation of the monothione
3 and subsequent sulfur extrusion gave fuligocandin A (2a)
as the required Z isomer (Figure 2). This compound has
recently been synthesized in six steps starting from azide
derivatives by Satish et al.18a and by Ishibashi et al.18b using
the Meyer-Schuster rearrangement; the Ishibashi group also
obtained fuligocandin B.
Figure 2). Under the conditions employed (DABCO, P(OMe)3,
90 °C) that successfully gave fuligocandin A, the indole N-pro-
tecting group was also removed; however, the racemic fuligo-
candin B was never isolated in more than 20% yield. Remarkably,
TLC analysis during the alkylation step indicated that the
episulfide contraction of the alkylated intermediate 14b pro-
ceeded very rapidly in hot DMSO in the absence of both base and
thiophile to give the N-protected fuligocandin B 15b in 57%
isolated yield. Likewise, contraction also proceeded thermally
when 14a was heated in DMSO, but the yield of 15a was,
however, slightly lower, i.e., 49%. To our knowledge, this is the
Employing the convergent route, outlined in Scheme 4, we
also obtained fuligocandin B (3) (as the required Z,E-isomer,
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Scheme 5. N-Deprotection Employing Sodium Thiopheno-
late
Table 1. Vinylogous Amides Obtained Using the Eschen-
moser Protocol As Outlined in Scheme 4
first example of a successful Eschenmoser episulfide contraction
leading to vinylogous amides in the absence of both base and
thiophile. After conversion of 14b to the N-protected fuligocan-
din B, cautious N-deprotection was accomplished by adding
Cs2CO3 and methanol to the reaction mixture. The choice of the
protecting group somewhat influenced the overall yield. Ulti-
mately, the use of a protecting phenylsulfonyl group gave
fuligocandin B (3) in an isolated yield of 40%, while the use of
a p-nitrophenylsulfonyl group resulted in a slightly better yield
(53%). The relatively low overall yield resulting from this
episulfide contraction is due to reversibility of the thioamide
alkylation reaction which could be observed by TLC analysis.
The specific rotations of compounds 1-3 were determined
and showed, somewhat surprisingly, that the chirality at C-11a
(Scheme 3) of both fuligocandines A and B was lost in the last
step. These racemizations probably occurred due to tautomer-
ization brought on by the basic reaction conditions. It is known
that similar pyrrolobenzodiazepines will racemize in the presence
of base,19 and this is also supported by the fact that compound
15b, when prepared under neutral, thermal contraction condi-
tions, was optically active, giving specific rotation of þ611;
subsequent deprotection under basic conditions (MeOH/Cs2CO3)
led to loss of optical activity in the product fuligocandin B. An
exceptionally mild deprotection strategy for 2- and 4-nitroben-
zenesulfonamides was developed by Fukuyama.30 This method
typically involves the use of thiolates in DMF, at room
temperature, to give amines in high yields. When deprotection
was attempted employing sodium thiophenolate in DMSO we
obtained fuligocandin B in optically active form (Scheme 5),
with a specific rotation of þ140 which is in agreement with
Nakatani et al.,1 who reported a value of þ149. Racemic
fuligocandin B was obtained when the N-deprotection was
initially carried out using equimolar amounts of sodium
hydride and thiophenol. Fortunately, the undesired racemiza-
tion could be prevented by employing 1 equiv of sodium hydride
and 2 equiv of thiophenol. Supposedly, the excess thiophenol
acts as a Brønsted acid and neutralizes the basic species, which is
formed as a result of protecting group removal.
a Yields of isolated, pure vinylogous amides. a = R = -CH3; b = R =
-C6H5; c = R = -p-biphenyl.
notable that attempts to obtain vinylogous amide 17c (entry 3)
gave complex reaction mixtures and compound 17c was never
isolated.
The desired C11/C12 Z-configurations within both fuligocan-
din A and B were confirmed by NOE studies which revealed the
expected through-space interactions between H1/H12 (Figure 2).
In case of fuligocandin B, C14/C15 E-configuration was established
by large (15.1 Hz) vicinal coupling constants in agreement with
NMR data reported by Nakatani et al.1 The Z-configuration of the
double bond was also confirmed in compounds 20c and 22b.
’ CONCLUSIONS
The alkaloids fuligocandin A and B have been synthesized in a
simple fashion, and a considerably improved procedure for the
Eschenmoser coupling has been invented.
’ EXPERIMENTAL SECTION
(S)-11-Thioxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo-
[1,2-a][1,4]diazepine-5-(10H)-one (12). To a MeCN solution
(200 mL) of 1 (4.0 g, 20 mmol) was added a reagent (2.3 g, 6 mmol)
produced by refluxing P4S10 in pyridine,21 and the mixture was heated to
60 °C for 3 h during which time a yellow precipitate was formed. The
reaction mixture was allowed to stand at room temperature overnight
in order to precipitate fully. The product was vacuum-filtered and
washed with a small amount of cold MeCN to give 12 (3.9 g, 85%) as a
After accomplishing the synthesis of racemic fuligocandin A
and optically active fuligocandin B, we investigated the general
applicability of this one-pot alkylation-sulfur extrusion protocol
to obtain various vinylogous amides starting from thioamides 12
and 16-19, and the results are summarized in Table 1. Second-
ary amides reacted well with primary halides to give vinylogous
amides, whereas experiments involving secondary halides, R-halo
esters and R-halo malonates gave poor yields or no reaction. It is
pale-yellow solid: mp 268-270 °C (lit.17a mp 253-254 °C); [R]23
D
þ971 (c 0.16, MeOH) [lit.17a [R]23D þ873 (c 1.026, DMSO)]; IR νmax
3170, 2979, 1616, 1602, 1477, 1374, 1271, 1141, 831, 813, 752,
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699 cm-1 ; 1H NMR (300 MHz, DMSO-d6) δ 1.89-1.94 (m, 1H),
1.99-2.16 (m, 2H), 2.84-2.94 (m, 1H), 3.40-3.50 (m, 1H),
3.53-3.60 (m, 1H), 4.27 (d, J = 6.11 Hz, 1H), 7.22-7.27 (m, 1H),
7.30-7.37 (m, 1H), 7.55-7.60 (m, 1H), 7.80-7.85 (m, 1H), 12.46
(br s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 22.7(t), 29.0 (t), 46.8
(t), 59.8 (d), 121.8 (d), 125.7 (d), 127.8 (s), 130.2 (d), 132.2
(d),136.5 (s),164.2 (s), 201.9 (s).
(m, 1H), 3.80-3.85 (m, 1H), 4.30 (dd, J = 7.9, 1.6 Hz, 1H), 5.30 (s, 1H),
7.02-7.05 (m,1H), 7.19-7.24 (m, 1H), 7.43-7.48 (m, 1H), 7.96-
7.98 (m, 1H), 12.6 (br s, 1H); 13C NMR (75.5 MHz, acetone-d6) δ ppm
23.6 (t), 27.2 (t), 30.0 (q), 47.2 (t), 55.6 (d), 91.4 (d), 122.4 (d),
124.8 (d), 127.3 (s), 131.4 (d), 132.8 (d), 137.2 (s), 159.3 (s), 165.9 (s),
198.4 (s).
These NMR data are in agreement with those previously reported by
Spiro[cyclopentane-1,20(10H)-quinazolin]-40(30H)-thione
(18). A reagent (0.96 g, 25 mmol) prepared from P4S10 and pyridine21
was added to a suspension of spiro[cyclopentane-1,20(10H)-quinazolin]-
40(30H)-one24 (1.0 g, 5 mmol) in acetonitrile (50 mL), and the reaction
mixture was heated at reflux for 7 h. After being cooled to room
temperature, the dark-red solution was poured into water and allowed to
stand in refrigerator overnight. The precipitate was collected and washed
with a small amount of cold MeCN to give 18 (0.97 g, 89%) as orange
flakes: mp 226 °C; IR νmax 3389, 3254, 3128, 2966, 1612, 1531, 1468,
Nakatani et al.1
1-(4-Nitrophenylsulfonyl)-3-carbaldehyde (8b). A CH2Cl2
suspension (120 mL) of indole-3-carbaldehyde (9.0 g, 0.062 mol, 1.0
equiv), DMAP (0.005 mol, 0.61 g, 0.08 equiv), and triethylamine (13 mL,
0.093 mol, 1.5 equiv) was stirred for 10 min at rt, and then 4-nitrophe-
nylsulfonyl chloride (15 g, 0.068 mol, 1.1 equiv) in 120 mLof CH2Cl2 was
added dropwise over 10 min. The reaction mixture was allowed to stir at
room temperature overnight and thereafter quenched with 300 mL of
HCl aq (5.0%). The phases were separated, and the water phase was
extracted several times with CH2Cl2. The red combined CH2Cl2 phases
were dried with Na2SO4 and flushed through a short silica plug.
Evaporation of the yellow filtrate in vacuo gave (20 g, 98%) 8b as a beige
solid: mp 160 °C (lit.26 mp 115 °C, this value seems to be in error); IR
νmax 3111, 1684, 1529, 1380, 1347, 1179, 1126, 973, 737 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ ppm 7.43 (t, J = 5.8 Hz, 1H), 7.49 (t, J = 5.6 Hz,
1H), 8.00 (d, J = 6.2 Hz, 1H), 8.13 (d, J = 5.9 Hz, 1H), 8.41 (s, 4H), 8.96
(s, 1H), 10.11 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ ppm 113.1
(d), 121.9 (d), 122.2 (s), 125.3 (d), 125.5 (d), 125.8 (s), 126.6 (d), 128.9
(d), 134.4 (s), 138.4 (d), 141.0 (s), 151.1 (s), 186.8 (d); HRMS (FAB)
m/z calcd for C15H10N2O5S [M þ H]þ 330.0310, found 330.0302.
(E)-1-Chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)but-3-en-
2-one (9a). A suspension of the protected indole-3-carbaldehyde 8a
(5.7 g, 0.02 mol, 1 equiv) in MeOH (100 mL) was heated for 30 min, and
then phosphorus ylide 6 (10.6 g, 0.03 mol, 1.5 equiv) was added (neat).
After 3 days of gentle reflux, the yellow suspension turned brown, and
the solvent was removed in vacuo to afford a brown semisolid crude
material which was purified by column chromatography (EtOAc/
heptane; 1:4) to give 5.40 g (69%) of 9a as a pale yellow solid: mp
154-155 °C; IR νmax 3137, 1708, 1613, 1446, 1360, 1174, 1131, 979,
744, 728 cm-1; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.77 (s, 2H),
7.13 (d, J = 16 Hz, 1H), 7.37-7.48 (m, 2H), 7.60-7.65 (m, 2H),
7.70-7.75 (m, 1H), 7.86 (d, J = 16 Hz, 1H), 7.99-8.01 (m, 1H),
8.04-8.13 (m, 3H), 8.56 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ
ppm 48.3 (t), 113.4 (d), 117.9 (s), 121.1 (d), 123.0 (d), 124.4 (d),
125.8 (d), 126.9 (d), 127.5 (s), 130.0 (d), 131.0 (d), 134.8 (d), 134.8
(s), 135.0 (d), 136.5 (s), 191. One (s).
1
1235, 1148, 994, 748 cm-1; H NMR (300 MHz, DMSO-d6) δ ppm
1.65-1.69 (m, 4H), 1.76-1.80 (m, 2H), 1.88-1.95 (m, 2H), 6.65-6.71
(2H, m), 7.08 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H),
10.29 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ ppm 22.2 (t), 38.5 (t),
77.1 (s), 114.8 (d), 116.9 (d), 119.4 (s), 131.4 (d), 133.7 (d), 143.6 (s),
188.5 (s). Anal. Calcd for C12H14N2S: C, 66.02; H, 6.46; N, 12.83. Found:
C, 65.92; H, 6.11; N, 12.53.
General Procedure for One-Pot Alkylation and Episulfide
Contraction. To a solution of thioamide (2 mmol, 1.00 equiv) in
DMSO (10 mL) was added NaH (95%) (22 mmol, 1.10 equiv), and the
mixture was stirred at room temperature for 30 min under argon. The
reaction mixture was treated with alkyl halide (1.05 mmol, 1.05 equiv),
and after 30 min of stirring at rt, trimethyl phosphite (66 mmol, 3 equiv)
and DABCO (66 mmol, 3 equiv) were added and the solution was
allowed to stir at 90 °C (internal temperature) until all alkylated species
were consumed according to TLC (2-14 h). (In cases when chlor-
oacetone was used as electrophile, 2 equiv of NaH and 2.5 equiv of
chloroacetone gave the best results. Aryl halides were usually added in
1.1 equiv amounts, but in some cases 1.00 or 1.10 equiv was used. The
actual amounts are specified below for each experiment.) After this time,
the reaction mixture was poured into distilled water (50 mL) and
extracted with CH2Cl2 (3 ꢀ 40 mL). The combined organic fractions
were washed with water (5 ꢀ 80 mL), dried over Na2SO4, and evaporated
under reduced pressure. Excess trimethyl phosphite and thioadducts were
removed by coevaporation with ethanol. Crude products were usually
solid, but in some cases the oily or semisolid crude material could be
precipitated by addition of ethanol. Crude products were recrystallized
from ethanol and oily products where purified by flash chromatography
(EtOAc/Hep 1:4).
These NMR data are in agreement with those reported by Caballero
et al.27
(E)-1-Chloro-4-(1-(4-nitrophenylsulfonyl)-1H-indol-3-yl)but-
3-en-2-one (9b). Compound 9b was obtained by the same proce-
dure as described for 9a using the protected indole-3-carbaldehyde 8b
(0.02 mol, 6.3 g, 1 equiv) and the phosphorus ylide 6 (0.023 mol, 8.1 g,
1.2 equiv) in MeOH (100 mL). After the reaction, a solid orange material
appeared, and this precipitate was allowed to fully form during a few hours at
rt. The crude product was collected by filtration then stirred in MeOH for a
few minutes. Filtration of the orange solid gave (6.48 g, 80%) of 9b: mp
174-175 °C; IR νmax 3105, 1698, 1606, 1525, 1177, 1123, 1080, 984,
738 cm-1; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.76 (s, 2H), 7.15 (d,
J= 16 Hz, 1H), 7.40-7.51 (m, 2H), 7.85 (d, J= 16 Hz, 1H), 8.00-8.07 (m,
2H), 8.21-8.40 (m, 4H), 8.58 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
δ ppm 48.3 (t), 113.4 (d), 118.8 (s), 121.2 (d), 123.5 (d), 124.8 (d), 125.3
(d), 126.1 (d), 127.7 (s), 128.6 (d), 130.6 (d), 134.4 (d), 134.7 (s), 141.2
(s), 151.0 (s), 191.1 (s); HRMS (FAB) m/z calcd for C18H13ClN2O5S
[M þ H]þ 404.0234, found 404.0242.
Isolation of the Thioimidate (13). To a solution of thioamide
12 (0.46 g, 2 mmol, 1.00 equiv) in DMSO (10 mL) was added NaH
(95%) (4 mmol, 2 equiv) and the solution was stirred at room temperature
for 30 min under argon. Chloroacetone (5 mmol, 2.5 equiv) was added
(neat), and after 40 min, when TLC analysis showed that all starting
material had been consumed, water was added and the phases were
separated. The water phase was extracted with CH2Cl2 (3 ꢀ 20 mL), and
the combined organic phases were washed with water (5 ꢀ 100 mL) and
dried (Na2SO4). Evaporation of the crude mixture gave 13 as a yellow
glistening solid (0.58 g, 100%). Compound 13 is unstable and had to be
used immediately in the next step.
Fuligocandin A (2a). Prepared according to the general proce-
dure using the monothione 12 (0.46 g, 2 mmol, 1 equiv) and chloroa-
cetone (0.4 mL, 5 mmol, 2.5 equiv). Racemic fuligocandin A (2a) was
obtained as an off-white solid (0.5 g, 98%): mp 156-157 °C from ethanol
(lit.1 mp 140-144 °C); IR IR νmax 2984, 2877, 1631, 1592, 1557, 1405,
1263, 1252, 755, 733, 696 cm-1; 1H NMR (300 MHz acetone-d6) δ ppm
2.00-2.10 (m, 2H), 2.11-2.29 (m, 4H), 2.34-2.46 (m, 1H), 3.64-3.70
Fuligocandin B (3) from 9b and 12. To a solution of the
monothioamide 12 (1.0 mmol, 0.23 g, 1 equiv) in DMSO (5 mL) was
added NaH (95%) (1.0 mmol, 0.027 g, 1 equiv). The mixture was stirred
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at room temperature, and after 1 h, the indole derivative 9b (1.0 mmol,
0.41 g, 1.0 equiv) was added. After 2 h at room temperature, TLC
analysis still showed traces of starting materials; despite this fact, the
reaction mixture was heated (90 °C internal temperature) for 2 h. After
the mixture was cooled to room temperature (at this point, in place of
proceeding with workup, in situ deprotection could be carried out using
two different methods, namely (a) MeOH/Cs2CO3 and (b) sodium
thiophenolate; see below), distilled water (50 mL) was added to the dark
brown mixture and then extracted with CH2Cl2 several times. The
combined organic fractions were washed with water (5 ꢀ 50 mL), dried
over Na2SO4, and evaporated under reduced pressure. The brownish
crude material was purified using column chromatography EtOAc/
heptane (2:1) to yield 15b as a yellow solid (0.323 g, 57%): mp 175 °C
dec;[R]23D þ611 (c 0.19, MeOH); IRνmax 3642, 3463, 3100, 1636, 1596,
1531, 1348, 1176, 1122, 984, 854, 739, 562 cm-1, 1HNMR (300 MHz,
DMSO-d6) δ ppm 2.02-2.04 (m, 2H), 2.11-2.18 (m, 1H), 2.43-2.49
(m, 1H), 3.40-3.55 (m, 1H), 3.62-3.66 (m, 1H), 4.45 (dd, J = 7.2, 1.5 Hz,
1H), 5.90 (s, 1H), 7.18-7.26 (m, 3H), 7.42-7.48 (m, 2H), 7.51-7.58 (m,
1H), 7.69 (d, J = 16.1 Hz, 1H), 7.82-7.84 (m, 1H), 8.01-8.03 (m, 1H),
8.12-8.15 (m, 1H), 8.30-8.40 (m, 4H), 8.46 (s, 1H), 13.17 (s, 1H);
13CNMR (75.5 MHz, DMSO-d6) δ ppm 23.2 (t), 26.5 (t), 46.8 (t), 55.1
(d), 92.9 (d), 113.4 (d), 119.7 (s), 121.6 (d), 122.1 (d), 124.3 (d), 124.7
(d), 125.3 (d), 125.9 (d), 126.0 (d), 127.1 (s), 127.9 (s), 128.6 (d), 129.4
(d), 129.9 (d), 130.8 (d), 132.6 (d), 134.9 (s), 136.7 (s), 141.4 (s), 151.0
(s), 160.6 (s), 164.5 (s), 188.0 (s); HRMS (FAB) m/z calcd for C30H24-
N4O6S [M þ H]þ 568.1417, found 568.1438.
Isolation of N-Phenylsulfonyl-Protected Fuligocandin B
(15a). Compound 15a was prepared according to the above method;
however, the deprotection step was omitted, and after 2 h of heating at
90 °C water was added and the reaction mixture worked up as described
above. The crude product was purified using column chromatography
EtOAc/heptane (2:1) to yield 15a as a brown solid (0.26 g, 49%): mp
1
170 °C dec; HNMR (300 MHz, DMSO-d6) δ ppm 2.02-2.03 (m,
2H), 2.13-2.17 (m, 1H), 2.43-2.48 (m, 1H), 3.45-3.54 (m, 1H),
3.62-3.66 (m, 1H), 4.45 (dd, J = 7.5, 1.3 Hz, 1H), 5.90 (s, 1H), 7.19-
7.29 (m, 3H), 7.39-7.45 (m, 2H), 7.51-7.58 (m, 1H), 7.67-7.73 (m,
2H), 7.82-7.84 (m, 2H), 8.01-8.03 (m, 1H), 8.12-8.15 (m, 3H),
8.30-8.40 (m, 1H), 8.43 (s, 1H), 13.17 (s, 1H); 13C NMR (75.5 MHz,
DMSO-d6) δ ppm 23.2 (t), 26.5 (t), 46.8 (t), 55.0 (d), 93.0 (d), 113.4
(d), 118.8 (s), 121.5 (d), 122.1 (d), 124.2 (d), 124.3 (d), 125.7 (d),
126.9 (d), 127.1 (s), 127.7 (s), 128.4 (d), 129.3 (d), 130.1 (d), 130.3 (d),
130.8 (d), 132.6 (d), 134.9 (s), 135.0 (d), 136.6 (s), 136.7 (s), 160.5 (s),
164.6 (s), 188.2 (s); MS analysis for 15a was unsuccessful as attempts to
obtain molecular ion for this compound failed due to decomposition with
both EI, CI-CH4, and with CI-NH3.
(Z)-11-(2-Oxo-2-phenylethylidene)-2,3,11,11a-tetrahy-
dro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one
(2b). Prepared according to the general procedure using the mono-
thione 12 (0.23 g 1 mmol, 1 equiv), 2-bromo-1-phenylethanone (0.23 g,
1.1 mmol, 1.1 equiv), and appropriate amounts of solvents and reagents
to give 2b as a pale yellow solid (0.30 g, 93%): mp 179 °C; IR νmax 2971,
1
2874, 1634, 1592, 1549, 1482, 1266, 1253, 1166, 756, 733 cm-1; H
(a) Deprotection of 15b Using Cs2CO3 and MeOH. MeOH (4 mL)
and Cs2CO3 (3 mmol, 0.98 g, 3 equiv) were added to the reaction mixture
and the stirring continued at rt. The deprotection was complete after 1 h,
and the product could be observed as an intensively yellow band on a TLC
plate at 365 nm. Distilled water (50 mL) was added to the dark-red mixture
and the mixture extracted with CH2Cl2 several times. The combined
organic fractions were washed with water (5 ꢀ 50 mL), dried over Na2SO4,
and evaporated under reduced pressure. The brownish crude material was
purified using column chromatography EtOAc/heptane (1:1) to yield
racemic fuligocandin B (0.20 g, 53%) as a yellow pigment: mp 160 °C
dec; IR and NMR data are provided below.
NMR (300 MHz, DMSO-d6) δ ppm 2.02-2.06 (m, 2H), 2.06-2.19
(m, 1H), 2.62-2.67 (m, 1H), 3.49-3.52 (m, 1H), 3.62-3.67 (m, 1H),
4.49 (dd, J = 7.1, 1.4 Hz, 1H), 6.19 (s, 1H), 7.24-7.30 (m, 2H),
7.49-7.60 (m, 4H), 7.82-7.85 (m, 1H), 8.01-8.04 (m, 2H), 13.17 (s,
1H); 13C NMR (75.5 MHz, DMSO-d6) δ ppm 23.3 (t), 26.5 (t), 46.7
(t), 55.3 (d), 87.5 (d), 122.3 (d), 124.4 (d), 127.2 (s), 127.3 (d), 128.5
(d), 130.7 (d),131.8 (d), 132.5 (d), 136.6 (s), 138.8 (s), 161.3 (s), 164.5
(s), 189.6 (s). Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.11; H, 5.71; N, 8.62.
(Z)-11-(2-(Biphenyl-4-yl)-2-oxoethylidene)-2,3,11,11a-tetra-
hydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one
(2c). Prepared according to the general procedure using the thione 12
(0.23 g 1 mmol, 1 equiv), 1-(biphenyl-4-yl)-2-bromoethanone (0.29 g,
1.05 mmol, 1.05 equiv), and appropriate amounts of solvents and reagents
to give 2c as a yellow crystalline solid (0.35 g, 89%): mp 129-131 °C; IR
(b) Deprotection of 15b Using Thiophenolate. To a solution of
thiophenol (0.22 g, 2 mmol) in DMSO (1 mL) was added NaH (0.027 g,
1 mmol), and after being stirred for 3 min the solution was added to the
reaction mixture at rt. TLC analysis showed that the deprotection was
complete after 2 min, and the product could be observed as an
intensively yellow band at 365 nm. Distilled water (50 mL) was added
to the dark-red mixture and the mixture extracted with CH2Cl2 several
times. The combined organic fractions were washed with water (5 ꢀ
50 mL), dried over Na2SO4, and evaporated under reduced pressure.
The brownish crude material was purified using column chromatography
EtOAc/heptane (1:1) to yield optically active fuligocandin B (0.25 g, 65%)
νmax 3059, 2874, 1614, 1588, 1561, 1476, 1268, 1195, 1098, 752, 696 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ ppm 2.04-2.06 (m, 2H), 2.13- 2.26
(m, 1H), 2.66-2.70 (m, 1H), 3.43-3.56 (m, 1H), 3.63-3.69 (m, 1H),
4.50 (dd, J = 7.1, 1.3 Hz, 1H), 6.24 (s, 1H), 7.25-7.28 (m, 2H), 7.42-7.44
(m, 1H), 7.48-7.54 (m, 3H), 7.73-7.86 (m, 5H), 8.11-8.13 (m, 2H),
13.15 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ ppm 23.3 (t), 26.5 (t),
46.7 (t), 55.3 (d), 87.6 (d), 122.3 (d), 124.4 (d), 126.8 (d), 126.9 (s), 127.2
(d), 128.0 (d), 128.1 (d), 129.0 (d), 130.7 (d), 132.5 (d), 136.6 (s), 137.7
(s), 139.1 (s), 143.3 (s), 161.3 (s), 164.5 (s), 189.0 (s). Anal. Calcd for
C26H22N2O2: C, 79.17; H, 5.62; N, 7.10. Found: C, 79.22; H, 5.51; N, 6.98.
(Z)-1-(Biphenyl-4-yl)-2-(pyrrolidin-2-ylidene)ethanone
(20c). Prepared according to the general procedure using thione 16
(0.10 g 1 mmol, 1 equiv), 1-(biphenyl-4-yl)-2-bromoethanone (0.30 g,
1.1 mmol, 1.1 equiv), and appropriate amounts of solvents and reagents to
give 20c as a beige solid (0.27 g, 85%): mp 186-187 °C; IR νmax 3297,
2879, 1600, 1564, 1524, 1296, 1258, 1041, 854, 746, 692 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.39-148 (m, 2H), 2.22 (t, J = 8.09 Hz,
2H), 3.07 (t, J=6.94 Hz, 2H), 5.36 (s, 1H), 6.86-6.90 (m, 1H), 6.96-7.01
(m, 2H), 7.20-7.23 (m, 4H), 7.41-7.44 (m, 2H), 9.67 (s, 1H); 13C NMR
(75.5 MHz, DMSO-d6) δ ppm 20.9 (t), 32.8 (t), 47.7 (t), 85.4 (d), 126.5
(d), 126.8 (d), 127.3 (d), 127.8 (d), 129.0 (d), 138.9 (s), 139.5 (s), 141.9
(s), 168.7 (s), 184,8 (s). Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N,
5.32. Found: C, 81.92; H, 6.32; 5.06.
as a yellow pigment: mp 160 °Cdec;[R]23D þ 140 (c 0.5, MeOH) ([R]23
D
þ149 (c 0.6, MeOH)); IR νma1x 3222, 2950, 1590, 1565, 1456, 1269, 1131,
1102, 1084, 740, 590 cm-1; H NMR (300 MHz, acetone-d6) δ ppm
2.06-2.17 (m, 2H), 2.27-2.30 (m, 1H), 2.57-2.62 (m, 1H), 3.55-3.65
(m, 2H), 4.46 (dd, 1H, J = 8.0, 1.6 Hz), 5.82 (s, 1H), 7.02 (d, 1H, J =
15.1 Hz), 7.13-7.16 (m, 1H), 7.19-7.23 (m, 3H), 7.50-7.62 (m, 2H),
7.82-7.85 (m, 1H), 7.87-7.91 (m, 1H), 7.93 (d, 1H, J = 15.1 Hz),
8.02-8.05 (m, 1H), 10.9 (br s, 1H), 13.4 (br s, 1H); 13CNMR (75.5 MHz,
acetone-d6) δ ppm 24.1 (t), 29.0 (t), 47.6 (t), 56.2 (d), 93.6 (d), 113.0 (d),
114.1(s), 121.4 (d), 121.7 (d), 122.7 (d), 123.6 (d), 124.0 (d), 124.5 (d),
126.5 (s), 128.3 (s), 131.5 (d), 131.6 (d), 133.2 (d), 135.0 (d), 138.6 (s),
138.7 (s), 160.6 (s), 165.9 (s), 190.4 (s).
These NMR data are in agreement with those previously reported by
Nakatani et al.1
Fuligocandin B was also isolated by this method using thione 12 and
9a to give 0.17 g (44%) of the title compound.
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The Journal of Organic Chemistry
ARTICLE
(Z)-1-(10H-Spiro[cyclopentane-1,20-quinazoline]-40(30H)-yli-
dene)propan-2-one (22a). Prepared according to the general
procedure using the thione 18 (0.44 g 2 mmol, 1 equiv), chloroacetone
(0.4 mL, 5 mmol, 2.5 equiv), and appropriate amounts of solvents and
reagents to give 22a as a dark-red semisolid (0.40 g, 82%): IR νmax 3255,
2957, 1614, 1599, 1522, 1485, 1358, 1328, 1293, 1252 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.39-1.48 (m, 4H), 1.69-1.77 (m, 4H),
1.99 (s, 3H), 5.64 (s, 1H), 6.63-6.68 (m, 1H), 6.72-6.74 (m, 1H), 6.91
(s, 1H), 7.20-7.24 (m, 1H), 7.54-7.56 (m, 1H), 11.43 (s, 1H); 13C
NMR (75.5 MHz, DMSO-d6) δ ppm 21.8 (t), 29.1 (q), 38.9 (t), 74.2 (s),
87.5 (d), 113.6 (s), 115.5 (d), 117.3 (d), 125.0 (d), 132.6 (d), 145.9 (s),
153.8 (s), 193.6 (s). This compound starts to decompose in a matter of
hours at room temperature; thus, no elemental analysis was performed.
(Z)-1-Phenyl-2-(10H-spiro[cyclopentane-1,20-quinazoline]-
40(30H)-ylidene)ethanone (22b). Prepared according to the gen-
eral procedure using the thione 18 (0.44 g 2 mmol, 1 equiv), 2-bromo-
1-phenylethanone (0.44 g, 2.2 mmol, 1.1 equiv), and appropriate amounts
of solvents and reagents to give 22b as a dark yellow solid (0.49 g, 80%):
mp 171 °C; IR νmax 3298, 2948, 1613, 1592, 1513, 1350, 1149, 1024, 850,
749, 723, 684 cm-1; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.73-1.80
(m, 4H), 1.85-1.89 (m, 4H), 6.39 (s, 1H), 6.69-6.79 (m, 2H), 7.03 (s,
1H), 7.24-7.27 (m, 1H), 7.44-7.47 (m, 3H), 7.85-7.87 (m, 1H),
7.97-8.00 (m, 2H), 12.12 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ
ppm 21.9 (t), 39.1 (t), 74.4 (s), 84.1 (d), 114.0 (s), 115.5 (d), 117.4 (d),
125.7 (d), 126.8 (d), 128.2 (d), 129.3 (d), 133.0 (d), 140.3 (s), 146.0 (s),
155.9 (s), 186.2 (s). Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62; N,
9.20. Found: C, 78.52; H, 6.45; N, 9.16.
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jan.bergman@ki.se.
’ REFERENCES
(1) Nakatani, S.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.;
Ishibashi, M. Chem. Pharm. Bull. 2004, 52, 368–370.
(2) (a) Hasegawa, H.; Yasuaki, Y.; Komiyama, K.; Hayashi, M.;
Ishibashi, M.; Sunazuka, T.; Izuhara, T.; Sugahara, K.; Tsuruda, K.;
Masuda, M.; Takasu, N.; K. Tsukasaki, K.; Tomonaga, M.; Kamihira, S.
Blood 2007, 110, 1664–1674. (b) Ishibashi, M.; Ohtsuki, T. Med. Res.
Rev. 2008, 28, 688–714.
(3) Pettersson, B.; Hasimbegovic, V.; Bergman, J. Tetrahedron Lett.
2010, 5, 238–239.
(4) Michael, J. P.; de Koning, C. B.; Gravestock, D.; Hosken, G. D.;
Howard, A. S.; Jungmann, C. M; Krause, R. W. M.; Parsons, A. S.; Pelly,
S. C.; Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979–988.
(5) Knott, E. B. J. Chem. Soc. 1955, 916–927.
(6) Woodward, R. B. Pure Appl. Chem. 1968, 17, 519–47.
(7) (a) Roth, M.; Dubs, P.; Goetschi, E.; Eschenmoser, A. Helv.
Chim. Acta 1971, 54, 710–734. (b) Eschenmoser, A. Quart. Rev. Chem.
Soc. 1970, 24, 366–415.
(8) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069–
4078. Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313–6325.
Sardina, F. J.; Howard, M. H.; Morningstar, M.; Rapoport, H. J. Org.
Chem. 1990, 55, 5025–5033. Hernandez, A.; Rapoport, H. J. Org. Chem.
1994, 59, 1058–1066. Ireland, R. E.; Brown, F. R., Jr. J. Org. Chem. 1980,
45, 1868–1880. Pinnick, H. W.; Chang, Y.-H. J. Org. Chem. 1978, 43,
4662–4663. Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1982, 47, 4403–4409.
Howard, A. S.; Katz, R. B.; Michael, J. P. Tetrahedron Lett. 1983, 24, 829–
830.Michel, J. P.; Accone, C.; de Koning, C. B.; van der Westhuyzen,
C. W. Beil. J. Org. Chem. 2008, 4(5).
(9) Shiosaki, K. The Eschenmoser Coupling Reaction. In Compre-
hensive Organic Synthesis; Trost, B. M.; Heathcock, C. H., Eds.; Perga-
mon Press: Oxford, 1991; Vol. 2, pp 865-892.
(10) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VHC:
Weinheim, Germany, 1996; pp 99-136.
(11) Mulzer, J.; List, B.; Bats, J. W. J. Am. Chem. Soc. 1997, 119,
5512–5518.
(12) Michael, J. P.; de Konig, C. B.; van der Westuyzen, C. W.;
Fernandes, M. A. J. Chem. Soc., Perkin Trans. 1 2001, 2055–2063.
(13) Corsaro, A.; Perrini, G.; Testa, M. G.; Chiacchio, U. Phosphorus,
Sulfur Silicon 1992, 71, 197–206.
(14) Wright, W. B., Jr.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.;
Hardy, R. A., Jr. J. Med. Chem. 1978, 21, 1087–1089.
(Z)-1-(Biphenyl-4-yl)-2-(10H-spiro[cyclopentane-1,20-qui-
nazoline]-40(30H)-ylidene)ethanone (22c). Prepared according
to general procedure using the thione 18 (0.22 g 1 mmol, 1 equiv),
1-(biphenyl-4-yl)-2-bromoethanone (0.30 g, 1.1 mmol, 1.1 equiv),
and appropriate amounts of solvents and reagents to give 22c as a
dark yellow solid (0.31 g, 81%): mp 170 °C dec; IR νmax 3284, 2966,
1
1615, 1593, 1554, 1349, 1244, 1146, 1005, 856, 750, 698 cm-1; H
NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.81 (m, 4H), 1.88-1.90
(m, 4H), 6.45 (s, 1H), 6.71-6.80 (m, 2H), 7.05 (s, 1H), 7.26-7.28
(m, 1H), 7.39-7.42 (m, 1H), 7.46-7.51 (m, 3H), 7.72-7.75 (m,
4H), 7.88-7.91 (m, 1H), 8.07-8.10 (m, 2H), 12.16 (s, 1H); 13C
NMR (75.5 MHz, DMSO-d6) δ ppm 21.8 (t), 39.1 (t), 74.5 (s), 84.0
(d), 114.1 (s), 115.5 (d), 117.4 (d), 125.8 (d), 126.5 (d), 126.8 (d), 127.5
(d), 128.2 (d), 128.7 (d), 133.0 (d), 139.2 (s), 139.5 (s), 142.0 (s), 146.0
(s), 155.9 (s), 185.6 (s); HRMS (FAB) m/z calcd for C26H24N2O [M þ
H]þ 380.1889, found 380.1896.
(Z)-1-(Biphenyl-4-yl)-3-phenyl-3-(phenylamino)prop-2-en-
1-one (23c). Prepared according to the general procedure using the
thione 19 (0.21 g 1 mmol, 1 equiv), 1-(biphenyl-4-yl)-2-bromoethanone
(0.33 g, 1.05 mmol, 1.05 equiv), and appropriate amounts of solvents
and reagents to give 23c yellow glistening needles (0.32 g, 87%): mp
184-185 °C; IR νmax 3029, 1608, 1568, 1476, 1319, 1296, 1205, 1055,
761, 734, 688 cm-1; 1H NMR (300 MHz, DMSO-d6) δ ppm 6.26 (s,
1H), 6.84-6.86 (m, 2H), 7.00-7.05 (m, 1H), 7.16-7.21 (m, 2H), 7.41-
7.52 (m, 8H), 7.53-7.80 (m, 4H), 8.05-8.12 (m, 2H), 12.85 (s, 1H); 13C
NMR (75.5 MHz, DMSO-d6) δ ppm 96.7 (d), 123.0 (d), 124.2 (d), 127.2
(d), 127.2 (d), 128.0 (d), 128.3 (d), 128.5 (d), 128.6 (d), 1289 (d), 129.9
(d), 131.6 (d), 135.1 (s), 139.1 (s), 139.2 (s), 161.0 (s, 2C), 188.6 (s).
Anal. Calcd for C27H21NO: C, 86.37; H, 5.64; N, 3.73. Found: C, 86.22; H,
5.63; N, 3.52.
(15) Boeckman, R. K., Jr.; Zhang, J.; Reeder, M. R. Org. Lett. 2002, 4,
3891–3894.
(16) Bergman, J. Acta Chem. Scand. 1972, 26, 970–974.
(17) (a) Rekowski, M. v. W.; Pyriochou, A.; Papapetropoulos, N.;
Stossel, A.; Papapetropoulos, A.; Giannis, A. Bioorg. Med. Chem. 2010,
18, 1288–1296. (b) Schmidt, A.; Lindner, A. S.; Shilabin, A. G.; Nieger,
M. Tetrahedron 2008, 64, 2048–2056. (c) Kamal, A.; Howard, P. W.;
Reddy, N.; Reddy, P.; Thurston, D. E. Tetrahedron 1997, 53, 3223–
3230.
(18) (a) Satish, M. S.; Shanmughapriya, D.; Lingam, Y.; Patel, N. B.
Synth. Commun. 2009, 39, 2058–2066. (b) Arai, A. M.; Seto, J.; Ahmed,
F.; Uchiyama, K.; Ishibashi, M. Synlett 2008, 2498–2502.
(19) Lindner, S.; Schmidt, A. Synlett 2008, 2961–2964.
(20) Wu, X.; Liu, Y.; Sheng, W.; Sun, J.; Qin, G. Planta Med. 1997,
63, 55–57.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details for com-
b
pounds 1, 6, 8a, 10, and 12. Compound characterization data
for 1, 6, 8a, 10, 12, 16, 17, 20a,b, 21a,b, and 23a,b. Copies
(21) Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H.
J. Org. Chem. 2011, 75, DOI: 10.1021/jo101865y.
(22) Rae, I. D. Aust. J. Chem. 1979, 32, 567–573.
of H and 13C NMR spectra for all new compounds. This
1
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The Journal of Organic Chemistry
ARTICLE
(23) Ley, S.; Leach, A. G.; Storer, R. I. J. Chem. Soc., Perkin Trans. 1
2001, 358–361.
(24) Song, Y.-H. J. Heterocycl. Chem. 1998, 35, 1269–1273.
(25) Gribble, G. W.; Jiang, J.; Liu, Y. J. Org. Chem. 2002, 67, 1001–
1003.
(26) Aggarwal, R.; Benedetti, F.; Berti, F.; Buchini, S.; Colombatti,
A.; Dinon, F.; Galassi, V.; Norbedo, S. Chem.—Eur. J. 2003, 9, 3132–
3142.
(27) Caballero, E.; Alonso, D.; Pelaez, R.; Alvarez, C.; Puebla, P.;
Sanz, F.; Medarde, M.; Tome, F. Tetrahedron 2005, 61, 6871–6878.
(28) Delbecq, P.; Bacos, D.; Celerier, J. P.; Lhommet, G. Can. J.
Chem. 1991, 69, 1201–1206.
(29) Gonzalez-Nogal, A. M.; Calle, M. Eur. J. Org. Chem. 2007,
6089–6096.
(30) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373–6374.
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